HETEROARYLACETAMIDE INHIBITORS OF FACTOR Xa

ABSTRACT

The invention is concerned with novel heteroarylacetamides of formula (I) 
       R—C(O)—N(R e )—R c —CH 2 —C(O)—N(R a )(R b )   (I) 
     wherein R a  to R e  are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit the coagulation factor Xa and can be used as medicaments.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/301,560,filed Dec. 13, 2005, which claims the benefit of European ApplicationNo. 04106943.6, filed Dec. 23, 2004. The entire contents of theabove-identified applications are hereby incorporated by reference.

SUMMARY OF THE INVENTION

The invention is concerned with novel heteroarylacetamides of formula(I),

R^(d)—C(O)—N(R^(e))—R^(c)—CH₂—C(O)—N(R^(a))(R^(b))  (I)

wherein

R^(a) is hydrogen or C₁₋₆ alkyl;R^(b) is R^(b1)-R^(b2), wherein

R^(b1) is aryl or heteroaryl, said aryl and heteroaryl being optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl and halogen, and

R^(b2) is aryl, heteroaryl or heterocyclyl, said aryl, heteroaryl andheterocyclyl being optionally substituted by one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, halogen, cyano, nitro, amino, mono-or di-C₁₋₆ alkyl substituted amino, hydroxy, hydroxy C₁₋₆ alkyl,aminocarbonyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl, haloC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio,amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl,aminosulfonyl and mono- or di-C₁₋₆ alkyl substituted amino sulfonyl,

wherein one or two carbon atoms of said aryl, heteroaryl andheterocyclyl can optionally be replaced with a carbonyl group;orR^(a) and R^(b), together with the nitrogen atom to which they areattached, form heterocyclyl-A-R^(b3), wherein said heterocyclyl canoptionally be substituted by halogen or C₁₋₆ alkyl, and

A is a bond, —O— or C₁₋₆ alkylene wherein one —CH₂— can optionally bereplaced with a carbonyl group, and/or another —CH₂— can optionally bereplaced with —NR^(f)—, and

R^(b3) is amino optionally mono- or di-substituted by a substituentindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl, or

R^(b3) is aryl, heteroaryl, C₃₋₇ cycloalkyl or heterocyclyl, said aryl,heteroaryl, C₃₋₇ cycloalkyl and heterocyclyl being optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,halogen, cyano, nitro, amino, mono- or di-C₁₋₆ alkyl substituted amino,hydroxy, hydroxy C₁₋₆ alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkylsubstituted aminocarbonyl, halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkylsubstituted amino C₁₋₆ alkyl, aminosulfonyl and mono- or di-C₁₋₆ alkylsubstituted amino sulfonyl, wherein one or two carbon atoms of saidaryl, heteroaryl, C₃₋₇ cycloalkyl and heterocyclyl can optionally bereplaced with a carbonyl group;

R^(c) is heteroaryl optionally substituted by one or more substituentsindependently selected from the group consisting of halogen and C₁₋₆alkyl, wherein one or two carbon atoms of said heteroaryl can optionallybe replaced with a carbonyl group;

R^(d) is aryl, heteroaryl or heterocyclyl, said aryl, heteroaryl andheterocyclyl optionally being substituted by one or more substituentsindependently selected from the group consisting of halogen, C₁₋₆ alkyland C₁₋₆ alkoxy, and the aryl may be fused to a heterocyclyl ring;

R^(e) is hydrogen or C₁₋₆ alkyl;

R^(f) is hydrogen or C₁₋₆ alkyl;

and prodrugs and pharmaceutically acceptable salts thereof.

Further, the invention is concerned with a process for the manufactureof the above compounds, pharmaceutical preparations which contain suchcompounds as well as the use of these compounds for the production ofpharmaceutical preparations.

The compounds of formula (I) are active compounds that inhibit theactivity of coagulation factor Xa. These compounds consequentlyinfluence blood coagulation. They therefore inhibit the formation ofthrombi and can be used for the treatment and/or prevention ofthrombotic disorders, such as amongst others, arterial and venousthrombosis, deep vein thrombosis, peripheral arterial occlusive disease(PAOD), unstable angina pectoris, myocardial infarction, coronary arterydisease, pulmonary embolism, stroke (cerebral thrombosis) due to atrialfibrillation, inflammation and arteriosclerosis. They have potentiallybenefit in the treatment of acute vessel closure associated withthrombolytic therapy and restenosis, e.g. after transluminal coronaryangioplasty (PTCA) or bypass grafting of the coronary or peripheralarteries and in the maintenance of vascular access patency in long termhemodialysis patients. Factor Xa inhibitors of this invention may formpart of a combination therapy with an anticoagulant with a differentmode of action or with a platelet aggregation inhibitor or with athrombolytic agent. Furthermore, these compounds have an effect on tumorcells and prevent metastases. They can therefore also be used asantitumor agents.

Other inhibitors of factor Xa had previously been suggested for theinhibition of the formation of thrombi and for the treatment of relateddiseases. However, there is still a need for novel factor Xa inhibitorswhich exhibit improved pharmacological properties, e.g. an improvedselectivity towards thrombin.

The present invention provides novel compounds of formula (I) which arefactor Xa inhibitors. The compounds of the present inventionunexpectedly inhibit coagulation factor Xa and also exhibit improvedpharmacological properties compared to other compounds already known inthe art.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications, and publications cited herein areincorporated by reference in their entirety. In the event of a conflictin teaching, the present disclosure is controlling.

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

DEFINITIONS

The term “halogen” or “halo” means fluorine, chlorine, bromine andiodine, with fluorine, chlorine and bromine being preferred, andfluorine and chlorine being more preferred.

The term “C₁₋₆ alkyl”, alone or in combination with other groups, meansa branched or straight-chain monovalent alkyl radical, having one to sixcarbon atoms. This term is further exemplified by such radicals asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl. C₁₋₄alkyl is more preferred.

The term “C₁₋₆ alkylene” means a linear saturated divalent hydrocarbonradical of one to six carbon atoms or a branched saturated divalenthydrocarbon radical of three to six carbon atoms, e.g., methylene,ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene,pentylene.

The term “halo C₁₋₆ alkyl” means C₁₋₆ alkyl substituted by one or moresame or different halogen atoms independently selected from the groupconsisting of chlorine, fluorine and bromine. CF₃ is preferred.

The term “C₃₋₇ cycloalkyl”, alone or in combination with other groups,means a saturated monovalent cyclic hydrocarbon radical of three toseven ring carbons, e.g., cyclopropyl, cyclobutyl, cyclohexyl.

The term “C₁₋₆ alkoxy”, alone or in combination with other groups, meansthe group R′—O—, wherein R′ is a C₁₋₆ alkyl.

The term “C₂₋₆ alkenyl”, alone or in combination with other groups,means a straight-chain or branched hydrocarbon residue comprising anolefinic bond, having two to six carbon atoms, such as e.g. ethenyl,2-propenyl.

The term “C₂₋₆ alkynyl”, alone or in combination with other groups,means a straight-chain or branched hydrocarbon residue comprising atriple bond, having two to six carbon atoms, such as e.g. ethynyl,propynyl.

The term “aryl”, alone or in combination with other groups, means aphenyl or a naphthyl group, preferably a phenyl group.

The term “heterocyclyl”, alone or combination with other groups, meansnon-aromatic mono- or bi-cyclic radicals of three to eight ring atoms inwhich one or two ring atoms are heteroatoms selected from N, O, orS(O)_(n) (where n is an integer from 0 to 2), the remaining ring atomsbeing C.

The term “heteroaryl”, alone or combination with other groups, means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic ring containing one, two, or three ring heteroatoms selectedfrom N, O, and S, the remaining ring atoms being C, with theunderstanding that the attachment point of the heteroaryl radical willbe on an aromatic ring.

The term “mono-C₁₋₆ alkyl substituted amino” and “di-C₁₋₆ alkylsubstituted amino”, alone or combination with other groups, mean —NHRand —NRR′ respectively, in which R and R′ are the same or different C₁₋₆alkyl.

Preferred radicals for the chemical groups whose definitions are givenabove are those specifically exemplified in Examples.

Compounds of formula (I) can form pharmaceutically acceptable acidaddition salts. Examples of such pharmaceutically acceptable salts aresalts of compounds of formula (I) with physiologically compatiblemineral acids, such as hydrochloric acid, sulphuric acid, sulphurousacid or phosphoric acid; or with organic acids, such as methanesulphonicacid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroaceticacid, citric acid, fumaric acid, maleic acid, tartaric acid, succinicacid or salicylic acid. The term “pharmaceutically acceptable salts”refers to such salts. Compounds of formula (I) in which a COOH group ispresent can further form salts with bases. Examples of such salts arealkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca—and Trimethylammonium salts. The term “pharmaceutically acceptablesalts” also refers to such salts. Acid addition salts as described aboveare preferred.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “aryl group that can optionally besubstituted with an alkyl group” means that the alkyl may but need notbe present, and the description includes situations where the aryl groupis substituted with an alkyl group and situations where the aryl groupis not substituted with the alkyl group.

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, ifa carbon atom is bonded to four different groups, a pair of enantiomersis possible. An enantiomer can be characterized by the absoluteconfiguration of its asymmetric center and is described by the R- andS-sequencing rules of Cahn, Ingold and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The compounds of formula (I) can possess one or more asymmetric centers.Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art (see discussion in Chapter 4 of“Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons,New York, 1992).

While the broadest definition of this invention is described before,certain compounds of Formula (I) are preferred.

i) A preferred compound of the invention is a compound of Formula (I)wherein R^(a) and R^(b), together with the nitrogen atom to which theyare attached, form heterocyclyl-A-R^(b3), wherein said heterocyclyl canoptionally be substituted by halogen or C₁₋₆ alkyl, and A and R^(b3) areas defined before.

The heterocyclyl of heterocyclyl-A-R^(b3) is preferably piperazinyl orpiperidinyl, said piperazinyl and piperidinyl being optionallysubstituted by one or more substituents independently selected from thegroup consisting of halogen and C₁₋₆ alkyl, especially non substitutedpiperazinyl or non substituted piperidinyl. Piperazin-1-yl orpiperidin-1-yl, said piperazin-1-yl and piperidin-1-yl being bonded to-A-R^(b3) at 4-position is especially preferred.

A is preferably a bond or C₁₋₆ alkylene wherein one —CH₂— can optionallybe replaced with a carbonyl group, and/or another —CH₂— can optionallybe replaced with —NR^(f)—, in which R^(f) is hydrogen or C₁₋₆ alkyl. Ais more preferably a bond, methylene, ethylene, —CH₂—C(O)—, —C(O)—CH₂—or —C(O)—, especially a bond or —CH₂—C(O)—.

R^(b3) is preferably heterocyclyl optionally substituted by one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ alkoxy, amino, mono- or di-C₁₋₆ alkyl substituted amino,hydroxy, hydroxy C₁₋₆ alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkylsubstituted aminocarbonyl, halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, and one or two carbon atoms of saidheterocyclyl being optionally replaced with a carbonyl group.Heterocyclyl for R^(b3) is preferably one having a nitrogen as a ringmember atom, such as piperidinyl, pyrrolidinyl, morpholinyl, piperazinylor thiazolidinyl, said heterocyclyl group being optionally substitutedby one or more substituents, preferably one substituent independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, amino,mono- or di-C₁₋₆ alkyl substituted amino, hydroxy, hydroxy C₁₋₆ alkyl,aminocarbonyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl, haloC₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio, andone or two carbon atoms of said heterocyclyl group being optionallyreplaced with a carbonyl group.

Heterocyclyl for R^(b3) is more preferably pyrrolidinyl, piperidinyl orpiperazinyl, said heterocyclyl groups being unsubstituted or substitutedby one C₁₋₆ alkyl. Especially preferred are non substitutedpyrrolidin-1-yl and 1-methyl-piperidin-4-yl.

ii) Another preferred compound of the invention is a compound of Formula(I) wherein R^(a) is hydrogen or C₁₋₆ alkyl, and R^(b) is R^(b1)-R^(b2),wherein R^(b1) and R^(b2) are as defined before. R^(a) is preferablyhydrogen.

R^(b1) is preferably phenyl or pyridyl, said phenyl and pyridyl beingoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkyl and halogen, preferablyoptionally substituted by one halogen atom. R^(b1) is more preferablyphenyl optionally substituted by one or more halogen atoms, preferablyone halogen atom, especially fluorine.

R^(b2) is preferably aryl, heteroaryl or heterocyclyl, more preferablyheteroaryl or heterocyclyl, said aryl, heteroaryl and heterocyclyl beingoptionally substituted by one or more substituents, preferably onesubstituent independently selected from the group consisting of C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl,mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl, aminosulfonyl,mono- or di-C₁₋₆ alkyl substituted amino sulfonyl, and one or two carbonatoms of said aryl, heteroaryl and heterocyclyl being optionallyreplaced with a carbonyl group. A preferred aryl for R^(b2) is phenyloptionally substituted by one substituent selected from the groupconsisting of C₁₋₆ alkylsulfonyl, aminosulfonyl and mono- or di-C₁₋₆alkyl substituted amino sulfonyl.

R^(b2) is more preferably heteroaryl or heterocyclyl having a ringmember nitrogen atom bonded to R^(b1), said heteroaryl and heterocyclylbeing optionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkylsubstituted amino C₁₋₆ alkyl, aminosulfonyl and mono- or di-C₁₋₆ alkylsubstituted amino sulfonyl, and one or two carbon atoms of saidheteroaryl and heterocyclyl being optionally replaced with a carbonylgroup.

A preferred heteroaryl for R^(b2) is a mono cyclic heteroaryl having oneor two nitrogen atoms as a ring member such as pyridyl, imidazolyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, preferablypyridyl or imidazolyl, especially pyridyl. Preferably said heteroaryl isattached to R^(b1) via the nitrogen atom, and unsubstituted orsubstituted by amino C₁₋₆ alkyl or mono- or di-C₁₋₆ alkyl substitutedamino C₁₋₆ alkyl. Moreover, preferably one carbon atom of saidheteroaryl is replaced with a carbonyl group. 2-oxo-2H-pyridin-1-yl isespecially preferred.

A preferred heterocyclyl for R^(b2) is a mono cyclic heterocyclyl havingone nitrogen atom and, in addition to it, oxygen and/or sulphur atom asa ring member such as morpholinyl, 1,1-dioxo-thiazianyl,1,1-dioxo-isothiazolidinyl, 3-oxomorpholinyl. Preferably saidheterocyclyl is attached to R^(b1) via the nitrogen atom, andunsubstituted. In addition, preferably one carbon atom of theheterocyclyl for R^(b2) is replaced with a carbonyl group at theposition adjacent to the ring member atom attached to R^(b1), or theheterocyclyl for R^(b2) has —SO₂— as a ring member at the positionadjacent to the ring member atom attached to R^(b1).

iii) Another preferred compound of the invention is a compound ofFormula (I) wherein R^(e) is hydrogen.iv) Another preferred compound of the invention is a compound of Formula(I) wherein R^(c) is mono cyclic heteroaryl having a nitrogen atomand/or a sulphur atom as a ring member atom such as thiazolyl,pyrazolyl, triazolyl, tetrazolyl, pyridonyl. Triazolyl is especiallypreferred.v) Another preferred compound of the invention is a compound of Formula(I) wherein R^(d) is aryl, preferably phenyl, or heteroaryl, preferablythienyl, pyridyl or indolyl, especially thienyl, said aryl andheteroaryl being optionally substituted by one or more substituents,preferably one substituent, independently selected from the groupconsisting of halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy.

A preferred aryl for R^(d) is phenyl substituted by one halogen atomsuch as fluorine, bromine, chlorine, preferably chlorine. 4-chlorophenylis especially preferred.

A preferred heteroaryl for R^(d) is thienyl, pyridyl or indolyl, saidheteroaryls being optionally substituted by one halogen atom such asfluorine, bromine, chlorine, preferably chlorine. 5-chloro-thiophen-2-ylis especially preferred.

Particularly preferred compounds of the present invention are:

-   [4-(2-[1,4′]-Bipiperidinyl-1′-yl-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamide,-   N-{4-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,-   4-Chloro-N-{4-[2-(4-cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,-   4-Chloro-N-(4-{2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-{4-[2-(4-cyclopentyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,-   4-Chloro-N-(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-{4-[2-(4-dimethylcarbamoylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,-   4-Chloro-N-[4-(2-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,-   3-Fluoro-4-methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-[4-(2-{4-[2-(cyclohexylmethyl-amino)-acetyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   2,3-Dihydro-benzofuran-5-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   4-Chloro-N-(4-{2-oxo-2-[4-(2-pyrrolidin-1-yl-acetyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   5-Chloro-pyridine-2-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   4-Chloro-(RS)-[4-(2-{4-[2-(3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-(RS)-[4-(2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-[4-(2-{4-[2-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-[4-(2-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-[4-(2-{4-[2-(2,2-dimethyl-thiazolidin-3-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   4-Chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   N-{4-[(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide,-   (S)-1-[2-(4-{2-[2-(4-Chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic    acid dimethylamide,-   4-Chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamide,-   4-Chloro-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   Benzo[1,3]dioxole-5-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   5-Methyl-thiophene-2-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   5-Bromo-thiophene-2-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   4-Chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-(4-{[5-(2-methanesulfonyl-phenyl)-pyridin-2-ylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   (S)-1-[2-(4-{2-[2-(4-Chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic    acid methylamide,-   4-Chloro-[4-(2-{4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   N-{4-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,-   4-Chloro-[4-(2-{4-[2-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-[4-(2-{4-[2-((R)-3-ethoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,-   1H-Indole-6-carboxylic acid    (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,-   4-Chloro-3-fluoro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-(4-{2-oxo-2-[4-(2-oxo-2-thiazolidin-3-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   [4-(2-{4-[2-(3-Amino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamide,-   4-Chloro-[4-(2-oxo-2-{4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,-   4-Chloro-N-(4-{2-[4-(4,5-dihydro-thiazol-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   5-Bromo-thiophene-2-carboxylic acid    (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,-   3-Fluoro-4-methoxy-N!-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   4-Chloro-(4-{[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   4-Chloro-(4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   4-Chloro-(4-{[4-(1,1-dioxo-[1,2]thiazinan-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   4-Chloro-(4-{[4-(1,1-dioxo-isothiazolidin-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,-   5-Methyl-thiophene-2-carboxylic acid    (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,-   4-Chloro-(4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-amide,-   4-Chloro-N-(4-{2-oxo-2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-amide,-   4-Chloro-N-(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-benzamide,-   5-Chloro-thiophene-2-carboxylic acid    (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-amide,-   4-Chloro-N-(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-benzamide,-   5-Chloro-thiophene-2-carboxylic acid    (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-[1,2,4]triazol-3-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-[1,2,4]triazol-3-yl)-amide,-   5-Chloro-thiophene-2-carboxylic acid    (2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-2H-tetrazol-5-yl)-amide.

The compounds of the present invention can be prepared, for example, bythe general synthetic procedures described below.

General Synthetic Procedures

Abbreviations

BOP: Benzotriazolyl-N-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphateBOP-Cl: Bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chlorideDIPEA: Diisopropyl ethyl amine

DMF: N,N-Dimethylformamide

EDCI: N-(3-Dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloridePyBOP: Benzotriazol-1-yl-oxytripyrrolidinephosphoniumhexafluorophosphate

TEA: Triethylamine

TBTU: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumterafluoroborate

THF: Tetrahydrofurane 1. Synthesis of Thiazole Derivatives: Route A

R^(a) and R^(b) in the scheme are as defined before.

The starting acid is dissolved in a suitable solvent such as CH₂Cl₂,DMF, acetonitrile, THF and activated with an amide coupling reagent suchas BOP, BOP-Cl, TBTU, EDCI/DMAP in the presence of a base like TEA,DIPEA, N-methylmorpholine etc. at 0° C. to 50° C. After adding one totwo equivalents 2-(2-aminothiazol-4-yl)-ethyl acetate the correspondingamide is obtained after reaction for 0.5-120 h at 0° C. to 50° C.Preferred conditions are DMF, BOP and DIPEA.

Alkaline hydrolysis of intermediate I is effected by dissolving it in asuitable solvent like MeOH, EtOH, THF, 1,4-dioxane, water or mixturesthereof and a base like LiOH, NaOH, KOH, Na₂CO₃, K₂CO₃ or Cs₂CO₃.Preferred conditions are NaOH in EtOH/H₂O.

Intermediate II is then coupled with a primary or secondary amine oraniline HN(R^(a))(R^(b)) as described for the preparation ofintermediate I. Preferred conditions are DMF, BOP and DIPEA or CH₂Cl₂,TBTU and TEA.

2. Synthesis of Thiazole Derivatives: Route B

In the scheme shown above, R¹ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl and R² is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl C₁₋₆ alkyl or heterocyclyl, provided that R² can be C₃₋₇cycloalkyl C₁₋₆ alkyl or heterocyclyl, only when R¹ is hydrogen or C₁₋₆alkyl. R¹ and R², together with the nitrogen atom to which they areattached, may also form a heterocyclyl. Both the heterocyclyl for R² andthe heterocyclyl formed together by R¹, R², and the nitrogen atom towhich they are attached, may optionally be substituted by one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, halogen, cyano, nitro,amino, mono- or di-C₁₋₆ alkyl substituted amino, hydroxy, hydroxy C₁₋₆alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl,halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio,amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl,aminosulfonyl and mono- or di-C₁₋₆ alkyl substituted amino sulfonyl,wherein one or two carbon atoms of said heterocyclyl can optionally bereplaced with a carbonyl group.

Intermediate II is coupled with 1-(ethoxycarbonylmethyl)-piperazine asdescribed for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are DMF, BOP andDIPEA.

Alkaline hydrolysis of intermediate IV is effected as described for thepreparation of intermediate II in “1. Synthesis of thiazole derivatives:route A”. Preferred conditions are NaOH in H₂O/EtOH.

Intermediate V is coupled with a primary or secondary amine as describedfor the preparation of intermediate I in “1. Synthesis of thiazolederivatives: route A”.

Preferred conditions are DMF, BOP and DIPEA or CH₂Cl₂, TBTU and TEA.

3. Synthesis of Thiazole Derivatives: Route C

R^(d) in the scheme is as defined before.

The starting 2-(2-aminothiazol-4-yl)-ethyl acetate is converted to thet-butyloxycarbonyl protected amine by reacting it with Boc₂O in asuitable solvent such as dichloromethane, acetonitrile, THF, or DMF. Anadditive such as a catalytic amount of DMAP may be added. TheBoc-protected intermediate VII is obtained after reaction for 0.5-120 hat 0° C. to 50° C. Preferred conditions are CH₂Cl₂ and DMAP.

Alkaline hydrolysis of intermediate VII is effected as described for thepreparation of intermediate II in “1. Synthesis of thiazole derivatives:route A”. Preferred conditions are NaOH in H₂O/EtOH.

Intermediate VIII is coupled with1-(pyrrolidinocarbonylmethyl)piperazine as described for the preparationof intermediate I in “1. Synthesis of thiazole derivatives: route A”.Preferred conditions are CH₂Cl₂, TBTU and TEA.

Deprotection of intermediate IX is then effected by treatment with amineral acid such as HCl, HBr, H₂SO₄ or H₃PO₄ or a carbonic acid, in asolvent such as CH₂Cl₂, dioxane or HOAc at 0 to 60° C. Preferredconditions are 4N HCl in dioxane.

Intermediate X is then coupled with an aryl carboxylic acid R^(d)—COOHas described for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are EDCI, DMAP anddichloromethane.

4. Synthesis of Thiazole Derivatives: Route D

R^(d) in the scheme is as defined before.

Intermediate VIII is coupled with 1-(N-methylpiperidin-4-yl)piperazineas described for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are DMF, BOP andDIPEA.

Deprotection of intermediate XII is then effected by treatment with amineral acid such as HCl, HBr, H₂SO₄ or H₃PO₄ or a carbonic acid, in asolvent such as CH₂Cl₂, dioxane or HOAc at 0 to 60° C. Preferredconditions are HBr in HOAc.

Intermediate XIII is then coupled with an aryl carboxylic acidR^(d)—COOH as described for the preparation of intermediate I in “1.Synthesis of thiazole derivatives: route A”. Preferred conditions areEDCI, DMAP and dichloromethane.

5. Synthesis of Thiazole Derivatives: Route E

R^(a) and R^(b) in the scheme are as defined before.

The starting 5-chlorothiophene-2-carboxylic acid is coupled with2-(2-aminothiazol-4-yl)-ethyl acetate as described for the preparationof intermediate I in “1. Synthesis of thiazole derivatives: route A”.Preferred conditions are DMF, BOP and DIPEA.

Alkaline hydrolysis of intermediate XV is then effected as described forthe preparation of intermediate II in “1. Synthesis of thiazolederivatives: route A”. Preferred conditions are NaOH in H₂O/EtOH.

Intermediate XVI is coupled with an amine HN(R^(a))(R^(b)) as describedfor the preparation of intermediate I in “1. Synthesis of thiazolederivatives: route A”. Preferred conditions are DMF, BOP and DIPEA.

Alternatively, intermediate XV can be directly reacted with an anilineHN(R^(a))(R^(b)). Anilines are preactivated with AlMe₃ in a solvent suchas toluene or dioxane at r.t. and subsequently treated with ester XV atelevated temperature (usually 90° C.) to give the amide XVII.

6. Synthesis of Thiazole Derivatives: Route F

In the scheme shown above, R¹ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl and R² is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl C₁₋₆ alkyl or heterocyclyl, provided that R² can be C₃₋₇cycloalkyl C₁₋₆ alkyl or heterocyclyl, only when R¹ is hydrogen or C₁₋₆alkyl. R¹ and R², together with the nitrogen atom to which they areattached, may also form a heterocyclyl. Both the heterocyclyl for R² andthe heterocyclyl formed together by R¹, R², and the nitrogen atom towhich they are attached, may optionally be substituted by one or moresubstituents independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, halogen, cyano, nitro,amino, mono- or di-C₁₋₆ alkyl substituted amino, hydroxy, hydroxy C₁₋₆alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl,halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio,amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl,aminosulfonyl and mono- or di-C₁₋₆ alkyl substituted amino sulfonyl,wherein one or two carbon atoms of said heterocyclyl can optionally bereplaced with a carbonyl group.

Intermediate II is coupled with tert-butyl-1-piperazine carboxylate asdescribed for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are DMF, BOP andDIPEA.

Deprotection of intermediate XVIII is then effected by treatment with amineral acid such as HCl, HBr, H₂SO₄ or H₃PO₄ or a carbonic acid, in asolvent such as CH₂Cl₂, dioxane or HOAc at 0 to 60° C. Preferredconditions are 4N HCl in dioxane.

Intermediate XIX is coupled with glycine derivatives HOOC—CH₂—NR¹R² asdescribed for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are DMF, BOP andDIPEA.

Alternatively intermediate XIX is coupled with bromo acetic acid asdescribed for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions are DMF, BOP andDIPEA. The resulting α-bromoacetic acid amide is then treated with anexcess of a primary or secondary amine in a suitable solvent such asCH₂Cl₂, THF, acetonitrile etc. in the presence of an organic base suchas TEA, DIPEA etc. and reacted for 0.5-120 h at −20° C. to 50° C.

7. Synthesis of Pyrazole, Triazole and Tetrazole Derivatives

R^(a), R^(b) and R^(d) in the scheme are as defined before. Both X and Yare CH or both X and Y are N or X is N and Y is CH, and R′ is methyl orethyl.

The starting heterocycle is deprotonated with a base such as NaH orKOtBu in a suitable solvent such as DMF. Alternatively, a combination ofKOH in MeOH may be used. The anion is reacted with a suitable alkylatingagent such as ethyl iodoacetate, ethyl bromoacetate or methylchloroacetate for 0.5-120 h at 0° C. to 50° C.

Intermediate XXII is coupled with an aryl carboxylic acid R^(d)—COOH asdescribed for the preparation of intermediate I in “1. Synthesis ofthiazole derivatives: route A”. Preferred conditions aredichloromethane, EDCI/DMAP and TEA.

Alkaline hydrolysis of intermediate XXIII is then effected as describedfor the preparation of intermediate II in “1. Synthesis of thiazolederivatives: route A”. Preferred conditions are NaOH in H₂O/EtOH.

Intermediate XXIV is coupled with an amine HN(R^(a))(R^(b)) as describedfor the preparation of intermediate I in “1. Synthesis of thiazolederivatives: route A” to give amide XXV. Preferred conditions are DMF,BOP and DIPEA or MeCN, BOP-Cl and DIPEA.

Alternatively, intermediate XXIII can be directly reacted with ananiline HN(R^(a))(R^(b)). Anilines are preactivated with AlMe₃ in asolvent such as toluene or dioxane at r.t. and subsequently treated withester XXIII at elevated temperature (usually 90° C.) to give the amideXXV.

8. Synthesis of Pyridone Derivatives

R^(a), R^(b) and R^(d) in the scheme are as defined before.

Bromoacetic acid bromide is reacted with an amine HN(R^(a))(R^(b)) in asolvent such as THF, acetonitrile or CH₂Cl₂ in the presence of a organicbase such as triethylamine or DIPEA for 0.5-120 h at 0° C. to 50° C.

3-Nitro-pyridone is deprotonated with a base such as NaH or KOtBu in asuitable solvent such as DMF. The anion is reacted with bromide XXVI for0.5-120 h at 0° C. to 50° C. The nitro group of intermediate XXVII isthen reduced, preferably with zinc in acetic acid. Intermediate XXVIIIis coupled with an aryl acetic acid R^(d)—COOH as described for thepreparation of intermediate I in “1. Synthesis of thiazole derivatives:route A”. Preferred conditions are BOP, DIPEA and DMF.

As described above, the compounds of formula (I) are active compoundsand inhibit the coagulation factor Xa. These compounds consequentlyinfluence both platelet activation which is induced by this factor andplasmatic blood coagulation. They therefore inhibit the formation ofthrombi and can be used for the treatment and/or prevention ofthrombotic disorders, such as, amongst others, arterial and venousthrombosis, deep vein thrombosis, peripheral arterial occlusive disease(PAOD), unstable angina pectoris, myocardial infarction, coronary arterydisease, pulmonary embolism, stroke (cerebral thrombosis) due to atrialfibrillation, inflammation and arteriosclerosis. The compounds of thepresent invention can also be used in the treatment of acute vesselclosure associated with thrombolytic therapy and restenosis, e.g. aftertransluminal coronary angioplasty (PTCA) or bypass grafting of thecoronary or peripheral arteries and in the maintenance of vascularaccess patency in long term hemodialysis patients. F.Xa inhibitors ofthis invention may form part of a combination therapy with ananticoagulant with a different mode of action or with a plateletaggregation inhibitor or with a thrombolytic agent. Furthermore, thesecompounds have an effect on tumor cells and prevent metastases. They cantherefore also be used as antitumor agents.

Prevention and/or treatment of thrombotic disorders, particularlyarterial or deep vein thrombosis, is the preferred indication.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptableexcipient.

The invention likewise embraces compounds as described above for use astherapeutically active substances, especially as therapeutically activesubstances for the treatment and/or prophylaxis of diseases which areassociated with the coagulation factor Xa, particularly astherapeutically active substances for the treatment and/or prophylaxisof thrombotic disorders, arterial thrombosis, venous thrombosis, deepvein thrombosis, peripheral arterial occlusive disease, unstable anginapectoris, myocardial infarction, coronary artery disease, pulmonaryembolism, stroke due to atrial fibrillation, inflammation,arteriosclerosis, acute vessel closure associated with thrombolytictherapy or restenosis, and/or tumor.

In another preferred embodiment, the invention relates to a method forthe therapeutic and/or prophylactic treatment of diseases which areassociated with the coagulation factor Xa, particularly for thetherapeutic and/or prophylactic treatment of thrombotic disorders,arterial thrombosis, venous thrombosis, deep vein thrombosis, peripheralarterial occlusive disease, unstable angina pectoris, myocardialinfarction, coronary artery disease, pulmonary embolism, stroke due toatrial fibrillation, inflammation, arteriosclerosis, acute vesselclosure associated with thrombolytic therapy or restenosis, and/ortumor, which method comprises administering a compound as defined aboveto a human being or animal.

The inhibition of the coagulation factor Xa by the compounds of thepresent invention can be demonstrated with the aid of a chromogenicpeptide substrate assay as described hereinafter.

The activity of the low molecular weight substances can, moreover, becharacterized in the “prothrombin time” (PT) clotting test. Thesubstances are prepared as a 10 mM solution in DMSO and thereafter madeup to the desired dilution in the same solvent. Thereafter, 0.25 ml ofhuman plasma (obtained from whole blood anticoagulated with 1/10 volumeof 108 mM Na citrate) is placed in the instrument-specific samplecontainer. In each case 5 μl of each dilution of the substance-dilutionseries is then mixed with the plasma provided. This plasma/inhibitormixture is incubated at 37° C. for 2 minutes. Thereafter, 50 μl ofplasma/inhibitor mixture is pipetted to the semi-automatic device (ACL,Automated Coagulation Laboratory (Instrument Laboratory)) into themeasurement container. The clotting reaction is initiated by theaddition of 0.1 ml of Dade® Innovin® (recombinant human tissue factorcombined with calcium buffer and synthetic phospholipids, Dade Behring,Inc., Cat. B4212-50). The time up to the fibrin cross-linking isdetermined photooptically from the ACL. The inhibitor concentration,which brings about a doubling of the PT clotting time, is determined byfitting the data to an exponential regression (XLfit).

The compounds of the present invention can furthermore be characterisedby the Activated Partial Thromboplastin Time (aPTT). This coagulationtest can, e.g., be run on the ACL 300 Coagulation System(Instrumentation Laboratory) automatic analyzer. The substances areprepared as a 10 mM solution in DMSO and thereafter made up to thedesired dilution in the same solvent. The test is performed with theDade® Actin® FS Activated PTT reagent (purified soy phosphatides in1.0×10⁻⁴M ellagic acid, stabilizers and preservative, Dade Behring,Inc., Cat. B4218-100). Thereafter, 0.25 ml aliquots of human plasma(obtained from whole blood anticoagulated with 1/10 volume of 108 mM Nacitrate) are spiked with 5 μl of test compound in at least 6concentrations. 50 μl plasma at 4° C. containing 1/50 vol. inhibitor insolvent are incubated with 50 μl Dade® Actin® FS Activated PTT reagentin water at 37° C. for 3 min., then 50 μl CaCl2.2H2O 25 mM in water at37° C. are added. The time up to the fibrin cross-linking is determinedphotooptically from the ACL. The inhibitor concentration, which bringsabout a doubling of the APTT clotting time, is determined by fitting thedata to an exponential regression (XLfit).

The Ki values of the active compounds of the present invention arepreferably between about 0.001 and about 50 μM, especially between about0.001 and about 1 μM. The PT values are preferably between about 0.5 andabout 100 μM, especially between about 0.5 and about 10 μM. The aPTTvalues are preferably between about 0.5 and about 100 μM, especiallybetween about 0.5 and about 10 μM.

Ki [μM] Example factor Xa Ex. 37.5 0.062 Ex. 47.3 0.026 Ex. 61.4 0.006

The compounds of formula I and/or their pharmaceutically acceptablesalts can be used as medicaments, e.g. in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions, rectally, e.g. in the form of suppositories,parenterally, e.g. in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g. in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and/or theirpharmaceutically acceptable salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar. Suitable carriermaterials for injection solutions are, for example, water, alcohols,polyols, glycerol and vegetable oils. Suitable carrier materials forsuppositories are, for example, natural or hardened oils, waxes, fatsand semi-liquid or liquid polyols. Suitable carrier materials fortopical preparations are glycerides, semi-synthetic and syntheticglycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquidfatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 300 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g. in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES General Procedures

General Procedure A: Coupling of a Carboxylic Acid with an Amine UsingBop as a Coupling Reagent

To a stirred solution of the acid (1 eq) in DMF is added the amine(1.2-2 eq), N-ethyl-diisopropylamine (3-4 eq) and then BOP-reagent(1.2-1.5 eq). The mixture is stirred at r.t. under an argon atmospherefor 3-24 h. The mixture is diluted with EtOAc, washed with water andbrine, dried (MgSO₄), filtered and concentrated. The crude product canbe purified by chromatography (silicagel) or by crystallization.

General Procedure B: Coupling of a Carboxylic Acid with an Amine UsingBOP-Cl as a Coupling Reagent

To a stirred solution of the acid (1 eq) in MeCN is added the amine (1.1eq), N-ethyl-diisopropylamine (3 eq) and then BOP-Cl (1.05-2 eq). Themixture is stirred at r.t. under an argon atmosphere for 3-24 h. Themixture is diluted with EtOAc, washed with water and brine, dried(MgSO₄), filtered and concentrated. The crude product is purified bychromatography (silicagel).

General Procedure C: Coupling of a Carboxylic Acid with an Amine UsingTBTU as a Coupling Reagent

To a stirred solution of the acid (1 eq) in dichloromethane is added theamine (1.2 eq), triethylamine (2 eq) and then TBTU (1.2 eq). The mixtureis stirred at r.t. under an argon atmosphere for 3-24 h. The mixture isdiluted with dichloromethane, washed with saturated ammonium chloridesolution, water and brine, dried (MgSO₄), filtered and concentrated. Thecrude product is purified by chromatography (silicagel).

General Procedure D: Coupling of a Carboxylic Acid with an Amine UsingEDCI/DMAP as a Coupling Reagent

To a stirred solution of the amine (1 eq) in dichloromethane/DMF 3:1 isadded the acid (1.2 eq), triethylamine (2 eq), DMAP (0.5 eq) and thenEDCI (2 eq). The mixture is then stirred at r.t. under an argonatmosphere for 24-96 h, then evaporated to dryness. The residue is takenup in 1N NaOH and washed with EtOAc. The aqueous phase is extractedseveral times with CH₂Cl₂/MeOH 9:1. The organic layer is dried (MgSO₄),filtered and concentrated. The crude product is purified bychromatography (silicagel).

General Procedure E: Hydrolysis of a Carboxylic Acid Ester to theCorresponding Carboxylic Acid

The starting ester (1 eq) was dissolved in EtOH/H₂O 1:1 or MeOH/H₂O 1:1to give a 5-10% solution which was treated at 0° C. with solid NaOH (3eq). The reaction mixture was stirred at r.t. for 2-24 hrs. The EtOH wasremoved in the vacuum. The remaining aqueous solution was washed withdiethyl ether, then acidified with 3N HCl. In some case the productprecipitated upon acidification. In this case, the solid was filteredoff and dried in the high vacuum. If no precipitation occurred, theacidic aqueous layer was extracted with EtOAc. The organic layer waswashed with water and brine, then dried (MgSO₄). The product can bepurified by crystallization of by chromatography (silicagel).

General Procedure F: Conversion of a Carboxylic Acid Ester to an ArylAmide Using AlMe₃ Activation

The starting aniline (1.2-4 eq) was dissolved in toluene or dioxane togive a 5-10% solution which was treated under an argon atmosphere atr.t. with AlMe₃ in heptane (1.2-4 eq). The reaction mixture was stirredat r.t. 90 min. Then the ester (1 eq) was added. The temperature wasraised to 90°. Stirring was continued for 3-5 hrs. The reaction mixturewas cooled to r.t., then concentrated. The residue was taken up in EtOAcand washed with 1N HCl. The organic layer was dried (MgSO4), filteredand concentrated. The product can be purified by crystallization or bychromatography (silicagel).

Example 1

1.1 Using general procedure A, 4-chlorobenzoic acid and2-(2-aminothiazol-4-yl)-ethyl acetate were coupled to give[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester. Lightyellow solid. MS 325.3 ([M+H]⁺)

1.2 Using general procedure E,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester washydrolyzed to give [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid.Colorless solid. MS 295.5 ([M−H]⁻)

1.3 Using general method A,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid was coupled with4-piperidino piperidine give to[4-(2-[1,4′]-bipiperidinyl-1′-yl-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamide.Colorless solid. MS 447 ([M])

Example 2

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-benzyl-piperazine to giveN-{4-[2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,using general method A. Orange solid. MS 455.4 ([M+H]⁺)

Example 3

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with (1-cyclohexyl-methyl)piperazine to give4-chloro-N-{4-[2-(4-cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,using general procedure A. Colorless amorphous solid. MS 461.0 ([M+H]⁺)

Example 4

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(2-[4-morpholino]-ethyl)-piperazine to give4-chloro-N-(4-{2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,using general procedure A. Colorless amorphous solid. MS 478.1 ([M+H]⁺)

Example 5

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(pyrrolidinocarbonylmethyl)piperazine to give4-chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,using general procedure A. Off-white solid. MS 476.1 ([M+H]⁺)

Example 6

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-cyclopentyl-piperazine to give4-chloro-{4-[2-(4-cyclopentyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,using general procedure A. Off-white solid. MS 433.3 ([M+H]⁺)

Example 7

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(4-morpholido)-2-piperazinoethanone to give4-chloro-N-(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,using general procedure A. Amorphous off-white solid. MS 492.3 ([M+H]⁺)

Example 8

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with piperazino-acetic acid N,N-dimethylamide to give4-chloro-N-{4-[2-(4-dimethylcarbamoylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,using general procedure A. Amorphous white solid. MS 450.0 ([M+H]⁺)

Example 9

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) to give4-chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure B. Off-white solid. MS 483.3 ([M+H]⁺)

Example 10

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide(CAS 209919-51-7, prepared according to B.-Y. Zhu et al., patentapplication WO 2000071515) to giveN-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide,using general procedure C. White amorphous solid. MS 601.3 ([M+H]⁺)

A solution of 163 mgN-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamidein 8 ml CHCl₃/MeOH 3:1 was cooled to −11° C. A stream of HCl gas waspassed over the stirred solution for 10 min. The reaction mixture waskept at 4° C. over night, then concentrated. The crude product waspurified by chromatography on silica using a gradient from CH₂Cl₂ toCH₂Cl₂/MeOH 9:1 in 20 minutes to give 112 mg4-chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamideas white solid. MS 545.3 ([M+H]⁺)

Example 11

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(N-methylpiperidin-4-yl)piperazine to give4-chloro-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,using general procedure C. Off-white solid. MS 462.3 ([M+H]⁺)

Example 12

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 5-(2-methanesulfonyl-phenyl)-pyridin-2-ylamine,hydrochloride (CAS 209959-31-9) to give4-chloro-N-(4-{[5-(2-methanesulfonyl-phenyl)-pyridin-2-ylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure C. White solid. MS 527.2 ([M+H]⁺)

Example 13

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone hydrochloride(CAS 52548-39-7) to give4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,using general procedure C. White amorphous solid. MS 478.4 ([M+H]⁺)

Example 14

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with phenyl-piperazin-1-yl-methanone (CAS 13754-38-6) to giveN-{4-[2-(4-benzoyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,using general procedure C. White solid. MS 469.3 ([M+H]⁺)

Example 15

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 2-(piperazino)-2-thiazoline dihydrochloride to give4-chloro-N-(4-{2-[4-(4,5-dihydro-thiazol-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,using general procedure C. White solid. MS 450.0 ([M+H]⁺)

Example 16

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 2-(piperidin-4-yloxy)-pyridine dihydrochloride (CAS313490-36-7) to give4-chloro-N-(4-{2-oxo-2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,using general procedure C. White amorphous solid. MS 457.6 ([M+H]⁺)

Example 17

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylamine (CAS218301-68-9, prepared according to U.S. Ser. No. 02/38168) to give4-chloro-(4-{[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure A. Off-white solid. MS 511.4 ([M−H]⁻)

Example 18

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS742073-22-9) to give4-chloro-(4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure A. Off-white solid. MS 489.3 ([M+H]⁺)

Example 19

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 4-(1,1-dioxo-[1,2]thiazinan-2-yl)-phenylamine hydrochloride(CAS 37441-49-9) to give4-chloro-(4-{[4-(1,1-dioxo-[1,2]thiazinan-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure A. Yellow solid. MS 505.4 ([M+H]⁺)

Example 20

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 4-(1,1-dioxo-isothiazolidin-2-yl)-phenylamine, hydrochlorid(CAS 90556-91-5) to give4-chloro-(4-{[4-(1,1-dioxo-isothiazolidin-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,using general procedure A. Light yellow solid. MS 491.3 ([M+H]⁺)

Example 21

In analogy to example 1.3,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-methyl-4-(piperidin-4-yl)-piperazine to give4-chloro-(4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,using general procedure A. White solid. MS 462.4 ([M+H]⁺)

Example 22

22.1 Using general procedure A,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) wascoupled with 1-(ethoxycarbonylmethyl)-piperazine to give(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid ethyl ester. Off-white solid. MS 473.1 ([M+Na]⁺)

22.2 Using general procedure E,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid ethyl ester was hydrolyzed to(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid. Off-white solid. MS 423.1 ([M+H]⁺)

22.3 Using general procedure A,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid was coupled with 1-methyl piperazine to give4-chloro-N-[4-(2-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 505.3 ([M+H]⁺)

Example 23

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with 4-amino-1-methylpiperidine, usinggeneral method A, using THF instead of DMF as solvent, to give4-chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 519.3 ([M+H]⁺)

Example 24

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with 3-dimethylaminopyrrolidine, usinggeneral method A, using THF instead of DMF as solvent, to give4-chloro-(RS)-[4-(2-{4-[2-(3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Off-white solid. MS 519.5 ([M])

Example 25

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with 3-pyrrolidinol, using generalmethod A, using THF instead of DMF as solvent, to give4-chloro-(RS)-[4-(2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Off-white solid. MS 492.3 ([M])

Example 26

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with (R)-(−)-2-(hydroxmethyl)pyrrolidineusing general method A using THF instead of DMF as solvent to give4-chloro-[4-(2-{4-[2-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Off-white solid. MS 506.4 ([M])

Example 27

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with(S)-(+)-2-(hydroxmethyl)pyrrolidine, using general method A, using THFinstead of DMF as solvent, to give4-chloro-[4-(2-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Off-white solid. MS 506.4 ([M])

Example 28

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with 2,2-dimethylthiazolidine, usinggeneral method A, using THF instead of DMF as solvent, to give4-chloro-[4-(2-{4-[2-(2,2-dimethyl-thiazolidin-3-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 522.0 ([M])

Example 29

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with H-Pro-NMe₂, using general method C,to give(S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylicacid dimethylamide. Off-white solid. MS 547.5 ([M+H]⁺)

Example 30

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with nortropine, using general method C,to give4-chloro-[4-(2-{4-[2-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 532.3 ([M+H]⁺)

Example 31

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with (R)-3-ethoxy pyrrolidine, usinggeneral method C, to give4-chloro-[4-(2-{4-[2-((R)-3-ethoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Light yellow solid. MS 542.2 ([M+Na]⁺)

Example 32

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with thiazolidine, using general methodC, with PyBOP instead of TBTU as coupling reagent, to give4-chloro-(4-{2-oxo-2-[4-(2-oxo-2-thiazolidin-3-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide.Light yellow solid. MS 494.4 ([M+H]⁺)

Example 33

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with3-(tert-butyloxycarbonylamino)pyrrolidine, using general method C, togive{1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester. Off-white solid. MS 591.3 ([M+H]⁺)

A solution of 180 mg{1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester in 2 ml MeOH was cooled to 0° C., then treatedwith 1.5 ml 4M HCl in dioxane. The reaction mixture was stirred overnight at r.t., then concentrated. The residue was taken up in 5 ml 1Naqueous HCl and washed with diethylether. The aqueous layer was broughtto pH 12 with 4N NaOH and extracted with EtOAc, then with CH₂Cl₂/MeOH9:1. The combined organic layers were washed with brine, dried (MgSO₄),filtered and concentrated. The crude product was purified bychromatography on silica using a gradient from CH₂Cl₂ to CH₂Cl₂/MeOH85:15 in 20 min to give 25 mg[4-(2-{4-[2-(3-amino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamideas light yellow solid. MS 491.5 ([M+H]⁺)

Example 34

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with (S)-2-(trifluoromethyl)pyrrolidine,using general method C, to give4-chloro-[4-(2-oxo-2-{4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 543.8 ([M+H]⁺)

Example 35

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with H-Pro-NHMe, using general method C,to give(S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylicacid methylamide. White solid. MS 533.3 ([M+H]⁺)

Example 36

In analogy to example 22.3,(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-aceticacid (example 22.2) was coupled with (RS)-3-(methylsulfonyl)pyrrolidine,using general method C, to give4-chloro-(RS)-[4-(2-{4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.Off-white solid. MS 554.2 ([M+H]⁺)

Example 37

37.1 A solution of 30 g 2-(2-aminothiazol-4-yl)-ethyl acetate in 200 mlCH₂Cl₂ was treated at 0° C. with 2.9 g DMAP under an argon atmosphere. Asolution of 38.9 g Boc₂O in 50 ml CH₂Cl₂ was then added dropwise for 30min. The resulting suspension was stirred at r.t. overnight. Thereaction mixture was then washed with 5% aq. KHCO₃, H₂O, sat. aq. NH₄Cland brine, dried (MgSO₄), filtered and concentrated to leave the crudeproduct as a brown viscous oil. The product was isolated bychromatography on silica using EtOAc/cyclohexane 1:2 to give 40.5 g(2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester asorange viscous oil. MS 287.0 ([M+H]⁺)

37.2 Using general procedure E,(2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester washydrolyzed to (2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid.Colorless crystalline solid. MS 259.0 ([M+H]⁺)

37.3 Using general procedure C,(2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid was coupled with1-(pyrrolidinocarbonylmethyl)piperazine to give(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-carbamicacid tert-butyl ester. White solid. MS 460.4 ([M+Na]⁺)

37.4 In analogy to example 33,(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-carbamicacid tert-butyl ester was deprotected to give2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone.Off-white amorphous solid. MS 338.3 ([M+H]⁺)

37.5 Using general procedure D,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanonewas coupled with 5-chlorothiophene-2-carboxylic acid to give5-chloro-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Light yellow amorphous solid. MS 482.4 ([M+H]⁺)

Example 38

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 5-bromothiophene-2-carboxylic acid,using general method D, to give 5-bromo-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Light yellow solid. MS 528.1 ([M+H]⁺)

Example 39

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 5-methylthiophene-2-carboxylic acid,using general method D, to give 5-methyl-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Light yellow solid. MS 462.3 ([M+H]⁺)

Example 40

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with piperonylic acid, using general methodD, to give benzo[1,3]dioxole-5-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Off-white solid. MS 486.4 ([M+H]⁺)

Example 41

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with indole-6-carboxylic acid, using generalmethod D, to give 1H-indole-6-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Off-white solid. MS 481.5 ([M+H]⁺)

Example 42

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 4-chloro-3-fluorocarboxylic acid, usinggeneral method D, to give4-chloro-3-fluoro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide.Off-white solid. MS 494.5 ([M+H]⁺)

Example 43

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 3-fluoro-4-methoxycarboxylic acid, usinggeneral method D, to give3-fluoro-4-methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide.Light yellow solid. MS 490.4 ([M+H]⁺)

Example 44

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with p-anisic acid, using general method D,to give4-methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide.White solid. MS 472.3 ([M+H]⁺)

Example 45

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 5-chloro-pyridine-2-carboxylic acid,using general method D, to give 5-chloro-pyridine-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.Yellow solid. MS 477.3 ([M+H]⁺)

Example 46

In analogy to example 37.5,2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone(example 37.4) was coupled with 2,3-dihydrobenzofurane-5-carboxylicacid, using general method D, to give2,3-dihydro-benzofuran-5-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide.White solid. MS 506.5 ([M+Na]⁺)

Example 47

47.1 Using general method C,(2-tert-butoxycarbonylamino-thiazol-4-yl)-acetic acid (example 37.2) wascoupled with 1-(N-methylpiperidin-4-yl)piperazine to give(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamicacid tert-butyl ester. Off-white powder. MS 424.0 ([M+H]⁺)

47.2 To a stirred suspension of 3.9 g(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-carbamicacid tert-butyl ester was added 40 ml of 33% HBr in acetic acid. Thereaction mixture was stirred at r.t. for 4 h. The mixture was leftovernight in the fridge. Then it was concentrated to leave an off-whitesolid which was suspended in 50 ml Et₂O, triturated and stirred at r.t.for 3 h. The product was collected by filtration, washed with Et₂O anddried to give 5.6 g2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanonetrihydrobromide. Off-white solid. MS 324.4 ([M+H]⁺)

47.3 Using general procedure D,2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanonetrihydrobromide was coupled with 5-bromothiophene-2-carboxylic acid togive 5-bromo-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide.Yellow solid. MS 514.3 ([M+H]⁺)

Example 48

In analogy to example 47.3,2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanonetrihydrobromide (example 47.2) was coupled with5-chlorthiophene-2-carboxylic acid, using general method D, to give5-chloro-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide.Light orange solid. MS 468.5 ([M+H]⁺)

Example 49

In analogy to example 47.3,2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanonetrihydrobromide (example 47.2) was coupled with5-methylthiophene-2-carboxylic acid, using general method D, to give5-methyl-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide.Light yellow solid. MS 448.4 ([M+H]⁺)

Example 50

In analogy to example 47.3,2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanonetrihydrobromide (example 47.2) was coupled with3-fluoro-4-methoxybenzoic acid, using general method D, to give3-fluoro-4-methoxy-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide.Off-white amorphous solid. MS 476.3 ([M+H]⁺)

Example 51

51.1 Using general method A, 5-chlorothiophene-2-carboxylic acid andethyl-2-amino-4-thiazole acetate were coupled to give{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acidethyl ester. Off-white solid. MS 331.3 ([M+H]⁺)

51.2 Using general method F, 5-chlorothiophene-2-carboxylic acid andethyl-2-amino-4-thiazole acetate was reacted with1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, preparedaccording to C. F. Bigge et al., patent application WO 2003045912) togive 5-chloro-thiophene-2-carboxylic acid(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-amide.Light yellow solid. MS 489.3 ([M+H]⁺)

Example 52

In analogy to example 51.2,{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acidethyl ester (example 51.1) was reacted with4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 742073-22-9) to give{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acidethyl ester. Light yellow solid. MS 495.4 ([M+H]⁺)

Example 53

53.1 Using general method E,{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acidethyl ester (example 51.1) was hydrolyzed to give{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acid.Off-white solid. MS 301.0 ([M−H]⁻)

53.2 Using general method A,{2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acid wascoupled with 1-methyl-4-(piperidin-4-yl)-piperazine to give5-chloro-thiophene-2-carboxylic acid(4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide.Light yellow amorphous solid. MS 468.4 ([M+H]⁺)

Example 54

54.1 Using general method A, with THF instead of DMF as solvent,[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid ethyl ester(example 1.1) was coupled with tert-butyl-1-piperazine carboxylate togive4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester. White solid. MS 465.1 ([M+H]⁺)

54.2 In analogy to example 33,4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazine-1-carboxylicacid tert-butyl ester was deprotected to give4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 365.1 ([M+H]⁺)

54.3 Using general procedure A,4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide wascoupled with (2-oxo-pyrrolidine-1-yl)-acetic acid (CAS 53934-76-2) togive4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 490.4 ([M+H]⁺)

Example 55

55.1 Using general method A, with THF instead of DMF as solvent,4-chloro-N-[4-(2-oxo-2-piperazin-1-yl-ethyl)-thiazol-2-yl]-benzamide(example 54.2) was coupled with bromoacetic acid to giveN-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamide.Amorphous white solid.

55.2 To a stirred mixture of 100 mgN-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamidein 5 ml THF at r.t. were added 0.04 ml (aminomethyl)cyclohexane and 0.09ml triethylamine. After 48 hrs stirring at r.t. under argon atmosphere,the reaction mixture was concentrated. The crude product was purified bychromatography on silica using a gradient from CH₂Cl₂ to CH₂Cl₂/MeOH95:5 in 20 min to give 19 mg4-chloro-N-[4-(2-{4-[2-(cyclohexylmethyl-amino)-acetyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide.White solid. MS 518.5 ([M+H]⁺)

Example 56

In analogy to example 55.2,N-(4-{2-[4-(2-bromo-acetyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-4-chloro-benzamidewas reacted with pyrrolidine to give4-chloro-N-(4-{2-oxo-2-[4-(2-pyrrolidin-1-yl-acetyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide.Off-white amorphous solid. MS 476.0 ([M+H]⁺)

Example 57

57.1 To a stirred, cooled (0° C.) solution of the 1.6 g 3-aminopyrazolein DMF under an argon atmosphere was added potassium tert-butylate.After 30 min. stirring at 0° C., ethyl iodoacetate was added in oneportion. After 2 h stirring at 0° C., the ice bath was removed andstirring at r.t. was continued for 22 h. The mixture was concentrated inorder to remove as much DMF as possible. The residue was taken up inEtOAc and washed with H₂O. The aqueous phase was extracted with EtOAc.The combined organics were washed with H₂O and brine, dried (MgSO₄),filtered and concentrated. The crude product was purified bychromatography on silica using a gradient from cyclohexane to EtOAc in40 min to give 366 mg (3-amino-pyrazol-1-yl)-acetic acid ethyl ester asviscous yellow oil.

57.2 Using general method A, with THF instead of DMF as solvent,(3-amino-pyrazol-1-yl)-acetic acid ethyl ester was coupled with5-chlorothiophene-2-carboxylic acid to give{3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acidethyl ester. Light yellow solid. MS 314.0 ([M+H]⁺)

57.3 Using general method E,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acidethyl ester was hydrolyzed to give{3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid.Off-white powder. MS 284.0 ([M−H]⁻)

57.4 According to general method B,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid wasreacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-amide.White solid. MS 472.4 ([M+H]⁺)

Example 58

Using general method A, using THF instead of DMF as solvent,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid(example 57.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazine togive 5-chloro-thiophene-2-carboxylic acid(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-amide.Off-white solid. MS 451.3 ([M+H]⁺)

Example 59

59.1 Using general method A, with THF instead of DMF as solvent,(3-amino-pyrazol-1-yl)-acetic acid ethyl ester (example 57.1) wascoupled with 4-chlorobenzoic acid to give[3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid ethyl ester.Off-white solid. MS 308.3 ([M+H]⁺)

59.2 Using general method E,[3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid ethyl ester washydrolyzed to give [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid.White powder. MS 278.0 ([M−H]⁻)

59.3 According to general method B,[3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid was reacted with1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, preparedaccording to C. F. Bigge et al., patent application WO 2003045912) togive4-chloro-N-(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-benzamide.White solid. MS 466.3 ([M+H]⁺)

Example 60

Using general method A, using THF instead of DMF as solvent,[3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid (example 59.2) wasreacted with 1-(N-methyl-4-piperidyl)-piperazine to give4-chloro-N-(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-benzamide.Off-white solid. MS 445.4 ([M+H]⁺)

Example 61

61.1 To a stirred mixture of 2.8 g 3-amino-1,2,4-triazole in 50 ml DMF,1.57 g NaH were slowly added at 0° C. under an argon atmosphere. After 1hr stirring at 0° C., 3.31 ml ethyliodoacetate were added. The reactionmixture was stirred at r.t. over night. The mixture was diluted withwater and extracted with EtOAc and CH₂Cl₂/MeOH 9:1. The organic phasewas dried (MgSO4), filtered and concentrated. The crude product waspurified by chromatography on silica, using a gradient from CH₂Cl₂ toCH₂Cl₂/MeOH 9:1 and then crystallization from cyclohexane/EtOAc to give750 mg (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester as a whitesolid.

61.2 Using general method A, (3-amino-[1,2,4]triazol-1-yl)-acetic acidethyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give{3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-aceticacid ethyl ester. Off-white solid. MS 315.1 ([M+H]⁺)

61.3 Using general method E,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-aceticacid ethyl ester was hydrolyzed to give{3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-aceticacid. Off-white powder. MS 285.0 ([M−H]⁻)

61.4 According to general method B,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-aceticacid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) to give 5-chloro-thiophene-2-carboxylic acid(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-[1,2,4]triazol-3-yl)-amide.Off-white solid. MS 473.4 ([M+H]⁺)

Example 62

Using general method A, using THF instead of DMF as solvent,{3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-aceticacid (example 61.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazineto give 5-chloro-thiophene-2-carboxylic acid(1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-[1,2,4]triazol-3-yl)-amide.Off-white solid. MS 452.3 ([M+H]⁺)

Example 63

63.1 A solution of 8.5 g 5-amino-1H-tetrazole, 8.8 ml methylchloroacetate and 5.8 g potassium hydroxide in 100 ml methanol washeated to reflux under an argon atmosphere and stirred for 18 h. A whitesolid slowly precipitated. The suspension was cooled to r.t. The whitesolid was filtered off and washed with methanol. The filtrate wasconcentrated. The residue was suspended in 100 ml EtOH and heated toreflux. After 1 h stirring at reflux, the mixture was filtered whilehot. The filtrate was concentrated. The residue was recrystallized in100 ml EtOH to give 1.8 g of (5-amino-tetrazol-2-yl)-acetic acid methylester as colorless crystalline solid.

63.2 Using general method D, (5-amino-tetrazol-2-yl)-acetic acid methylester was coupled with 5-chlorothiophene-2-carboxylic acid to give{5-[(5-chloro-thiophene-2-carbonyl)-amino]-tetrazol-2-yl}-acetic acidmethyl ester. White solid. MS 302.0 ([M+H]⁺)

63.3 Using general method F,{5-[(5-chloro-thiophene-2-carbonyl)-amino]-tetrazol-2-yl}-acetic acidmethyl ester was reacted with1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, preparedaccording to C. F. Bigge et al., patent application WO 2003045912) togive 5-chloro-thiophene-2-carboxylic acid(2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-2H-tetrazol-5-yl)-amide.Off-white solid. MS 474.3 ([M+H]⁺)

Example 64

64.1 A solution of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS536747-52-1, prepared according to C. F. Bigge et al., patentapplication WO 2003045912) in 150 ml THF was treated with 5.8 mltriethylamine and 3.2 ml bromoacetyl bromide. The reaction mixture wasstirred overnight at r.t., then again treated with 2.1 ml bromoacetylbromide. After stirring overnight at r.t., the solid was filtered offand washed with THF. Then it was dissolved 11 EtOAc and washed 2× with100 ml H₂O. The organic layer was dried over MgSO₄, filtered andconcentrated to give 3.0 g2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide as off-whitesolid. MS 325.1 ([M+H]⁺)

64.2 A suspension of 34 mg sodium hydride in 2 ml DMF was cooled to 0°C. and treated portionwise with 100 mg of 2-hydroxy-3-nitropyridine. Thereaction mixture was stirred for 30 min, then treated at 0° C. with0.244 mg 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide. Thereaction mixture was stirred over night at r.t., then diluted with EtOAcand washed with water. The organic layer was dried (MgSO₄), filtered andconcentrated. The crude product was purified by chromatography (silicagel, gradient CH₂Cl₂->CH₂Cl₂/MeOH 95:5) to give 61 mg[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-2-(3-nitro-2-oxo-pyridin-1-yl)-acetamideas a light yellow solid. MS 385.1 ([M+H]⁺)

64.3 A suspension of 60 mg[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-2-(3-nitro-2-oxo-pyridin-1-yl)-acetamidein 1 ml acetic acid was treated portionwise with 82 mg activated zincpowder. The reaction mixture was stirred for 3 hrs at r.t. The solid wasfiltered off and washed carefully with EtOH. The filtrate wasconcentrated. The crude product was purified by chromatography (silica,gradient CH₂Cl₂->CH₂Cl₂/MeOH 95:5) to give 39 mg2-(3-amino-2-oxo-pyridin-1-yl)-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamideas off-white solid. MS 355.0 ([M+H]⁺)

64.4 Using general method A,2-(3-amino-2-oxo-pyridin-1-yl)-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamidewas reacted with 5-chloro-thiophene-2-carboxylic acid to give5-chloro-thiophene-2-carboxylic acid(1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl-carbamoyl]-methyl}-2-oxo-1,2-dihydro-pyridin-3-yl)-amide.Off-white solid. MS 499.3 ([M+H]⁺)

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcristallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg AceticAcid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titan dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mgMicrocristalline cellulose (AVICEL PH 102) 1400.0 mg Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mgMagnesiumstearate 10.0 mg Flavoring additives 1.0 mg

The active ingredient is mixed with lactose, microcristalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidon in water. The granulate is mixed withmagnesiumstearate and the flavouring additives and filled into sachets.

Example F

Factor Xa activity was measured spectrophotometrically in microtiterplates in a final volume of 150 μl using the following conditions:Inhibition of human factor Xa (Enzyme Research Laboratories) was testedat an enzyme concentration of 3 nM using the chromogenic substrateS-2222 (Chromogenix AB, Mölndal, Sweden) at 200 nM. The reactionkinetics of the enzyme and the substrate were linear with both time andthe enzyme concentration. The inhibitors were dissolved in DMSO andtested at various concentrations up to 100 μM. The inhibitors werediluted using HNPT buffer consisting of HEPES 100 mM, NaCl 140 mM, PEG6000 0.1% and Tween 80 0.02%, pH 7.8. The cleavage of S-2222 by humanfactor Xa was followed at 405 nm for 5 minutes at room temperature.

The velocity of the reaction was determined by the autoreader from theslope of the linear regression fit to 7 time points (1 minute). Theinitial velocity for each inhibitor concentration was determined by theslope of at least 4 time points in the linear phase by a linearregression fit (mOD/min²). Apparent dissociation constants K_(i) werecalculated according to Cheng and Prusoff [Cheng, Y. C.; Prusoff, W. H.Relationship between the inhibition constant (K_(i)) and theconcentration of the inhibitor that causes 50 percent inhibition (IC₅₀)of an enzyme reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.] basedon the IC₅₀ and the respective K_(m), determined previously(K_(i)=IC₅₀/(I+S/K_(m))). The K_(m) for the substrate used wasdetermined under the conditions of the test with at least 5 substrateconcentrations ranging from 0.5 to 15 times K_(m). [Lottenberg R, Hall JA, Blinder M, Binder E P, Jackson C M., The action of thrombin onpeptide p-nitroanilide substrates. Substrate selectivity and examinationof hydrolysis under different reaction conditions. Biochim Biophys Acta.1983 Feb. 15; 742(3):539-57]. According to Eadie [Eadie G. S. Theinhibition of cholinesterase by physostigmine and prostigmine. J. Biol.Chem. 1942, 146, 85-93.], the K_(m) for S-2222 amounted to 613 μM.

Ki [μM] Example factor Xa Ex. 37.5 0.062 Ex. 47.3 0.026 Ex. 61.4 0.006

1. A compound of formula (I):R^(d)—C(O)—N(R^(e))—R^(c)—CH₂—C(O)—N(R^(a))(R^(b))  (I) or apharmaceutically acceptable salt thereof, wherein: R^(a) is hydrogen orC₁₋₆ alkyl; and R^(b) is R^(b1)-R^(b2) wherein: R^(b1) is aryl orheteroaryl, wherein said aryl or heteroaryl is optionally substituted byone or more substituents independently selected from the groupconsisting of C₁₋₆ alkyl and halogen; and R^(b2) is aryl, heteroaryl orheterocyclyl, wherein one or two carbon atoms of said aryl, heteroarylor heterocyclyl is optionally replaced with a carbonyl group, andwherein said aryl, heteroaryl or heterocyclyl is optionally substitutedby one or more substituents independently selected from the groupconsisting of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,halogen, cyano, nitro, amino, mono- or di-C₁₋₆ alkyl substituted amino,hydroxy, hydroxy C₁₋₆ alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkylsubstituted aminocarbonyl, halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkylsubstituted amino C₁₋₆ alkyl, aminosulfonyl, and mono- or di-C₁₋₆ alkylsubstituted amino sulfonyl; or alternatively, R^(a) and R^(b), togetherwith the nitrogen atom to which they are attached, formheterocyclyl-A-R^(b3), wherein said heterocyclyl is optionallysubstituted by halogen or C₁₋₆ alkyl; wherein: A is a bond, —O— or C₁₋₆alkylene, wherein one —CH₂— of said C₁₋₆ alkylene is optionally replacedwith a carbonyl group, and another —CH₂— of said C₁₋₆ alkylene isoptionally replaced with —NR^(f)—; and R^(b3) is selected from the groupconsisting of: (1) amino, optionally mono- or di-substituted by asubstituent independently selected from the group consisting of C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl, (2) aryl, (3) heteroaryl, (4) C₃₋₇cycloalkyl and (5) heterocyclyl; wherein one or two carbon atoms of saidaryl, heteroaryl, C₃₋₇ cycloalkyl or heterocyclyl is optionally replacedwith a carbonyl group, and wherein said aryl, heteroaryl, C₃₋₇cycloalkyl or heterocyclyl is optionally substituted by one or moresubstituents independently selected from the group consisting of: C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, halogen, cyano, nitro,amino, mono- or di-C₁₋₆ alkyl substituted amino, hydroxy, hydroxy C₁₋₆alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkyl substituted aminocarbonyl,halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio,amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl,aminosulfonyl, and mono- or di-C₁₋₆ alkyl substituted amino sulfonyl;R^(c) is thiazole optionally substituted by one or more substituentsindependently selected from the group consisting of halogen and C₁₋₆alkyl; and one or two carbon atoms of said thiazole is optionallyreplaced with a carbonyl group; R^(d) is aryl, heteroaryl orheterocyclyl; wherein said aryl, heteroaryl or heterocyclyl isoptionally substituted by one or more substituents independentlyselected from the group consisting of halogen, C₁₋₆ alkyl and C₁₋₆alkoxy, and wherein said aryl is optionally fused to a heterocyclylring; R^(e) is hydrogen or C₁₋₆ alkyl; and R^(f) is hydrogen or C₁₋₆alkyl.
 2. A compound according to claim 1, wherein R^(a) and R^(b),together with the nitrogen atom to which they are attached, formheterocyclyl-A-R^(b3).
 3. A compound according to claim 2, wherein saidheterocyclyl of heterocyclyl-A-R^(b3) is piperazin-1-yl orpiperidin-1-yl bound to -A-R^(b3) at the 4-position.
 4. A compoundaccording to claim 2, wherein A is a bond or —CH₂—C(O)—.
 5. A compoundaccording to claim 2, wherein R^(b3) is heterocyclyl optionallysubstituted by one or more substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, mono- or di-C₁₋₆alkyl substituted amino, hydroxy, hydroxy C₁₋₆ alkyl, aminocarbonyl,mono- or di-C₁₋₆ alkyl substituted aminocarbonyl, halo C₁₋₆ alkyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, and C₁₋₆ alkylthio; wherein one ortwo carbon atoms of said heterocyclyl is optionally replaced with acarbonyl group.
 6. A compound according to claim 2, wherein R^(b3) is aheterocyclyl selected from the group consisting of piperidinyl,pyrrolidinyl, morpholinyl, piperazinyl and thiazolidinyl, wherein saidheterocyclyl is optionally be substituted by one or more substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆alkoxy, amino, mono- or di-C₁₋₆ alkyl substituted amino, hydroxy,hydroxy C₁₋₆ alkyl, aminocarbonyl, mono- or di-C₁₋₆ alkyl substitutedaminocarbonyl, halo C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,and C₁₋₆ alkylthio; wherein one or two carbon atoms of said heterocyclylis optionally replaced with a carbonyl group.
 7. A compound according toclaim 1, wherein R^(a) is hydrogen or C₁₋₆ alkyl, and R^(b) isR^(b1)-R^(b2).
 8. A compound according to claim 7, wherein R^(a) ishydrogen.
 9. A compound according to claim 7, wherein R^(b1) is phenyloptionally substituted by one or more halogen atoms.
 10. A compoundaccording to claim 7, wherein R^(b1) is fluorophenyl.
 11. A compoundaccording to claim 7, wherein R^(b2) is aryl, heteroaryl orheterocyclyl, wherein said aryl, heteroaryl or heterocyclyl isoptionally substituted by one or more substituents independentlyselected from the group consisting of C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl, mono- or di-C₁₋₆ alkylsubstituted amino C₁₋₆ alkyl, aminosulfonyl, and mono- or di-C₁₋₆ alkylsubstituted amino sulfonyl; wherein one or two carbon atoms of saidaryl, heteroaryl or heterocyclyl is optionally be replaced with acarbonyl group.
 12. A compound according to claim 7, wherein R^(b2) isheteroaryl or heterocyclyl, wherein said heteroaryl or heterocyclylcontains a nitrogen atom as a ring member which is bonded to R^(b1);wherein said R^(b2) can optionally be substituted by one or moresubstituents independently selected from the group consisting of C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylthio, amino C₁₋₆ alkyl,mono- or di-C₁₋₆ alkyl substituted amino C₁₋₆ alkyl, aminosulfonyl, andmono- or di-C₁₋₆ alkyl substituted amino sulfonyl; wherein one or twocarbon atoms of said heteroaryl or heterocyclyl is optionally replacedwith a carbonyl group.
 13. A compound according to claim 1 wherein R^(e)is hydrogen.
 14. A compound according to claim 1, wherein R^(c) isunsubstituted thiazole.
 15. A compound according to claim 1, whereinR^(d) is phenyl or thienyl, wherein said phenyl or thienyl is optionallysubstituted by one or more substituents independently selected from thegroup consisting of halogen, C₁₋₆ alkyl and C₁₋₆ alkoxy.
 16. A compoundaccording to claim 1, wherein R^(d) is chlorophenyl or chlorothienyl.17. A compound according to claim 1, selected from the group consistingof:[4-(2-[1,4′]-Bipiperidinyl-1′-yl-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamide,N-{4-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,4-Chloro-N-{4-[2-(4-cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,4-Chloro-N-(4-{2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-{4-[2-(4-cyclopentyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,4-Chloro-N-(4-{2-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-N-{4-[2-(4-dimethylcarbamoylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide,4-Chloro-N-[4-(2-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-[4-(2-{4-[(1-methyl-piperidin-4-ylcarbamoyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,3-Fluoro-4-methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-N-[4-(2-{4-[2-(cyclohexylmethyl-amino)-acetyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Methoxy-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,5-Chloro-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,5-Chloro-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,2,3-Dihydro-benzofuran-5-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,4-Chloro-N-(4-{2-oxo-2-[4-(2-pyrrolidin-1-yl-acetyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,and any pharmaceutically acceptable salt thereof.
 18. A compoundaccording to claim 1, selected from the group consisting of:5-Chloro-pyridine-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,4-Chloro-(RS)-[4-(2-{4-[2-(3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-(RS)-[4-(2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-[4-(2-{4-[2-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-[4-(2-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-[4-(2-{4-[2-(2,2-dimethyl-thiazolidin-3-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,4-Chloro-N-(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,N-{4-[(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide,(S)-1-[2-(4-{2-[2-(4-Chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylicacid dimethylamide,4-Chloro-N-{4-[(3-fluoro-2′-sulfamoyl-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-benzamide,4-Chloro-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,Benzo[1,3]dioxole-5-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,5-Methyl-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,5-Bromo-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,4-Chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-(4-{[5-(2-methanesulfonyl-phenyl)-pyridin-2-ylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,(S)-1-[2-(4-{2-[2-(4-Chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylicacid methylamide,4-Chloro-[4-(2-{4-[2-(3-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,N-{4-[2-(4-Benzoyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-4-chloro-benzamide,and any pharmaceutically acceptable salt thereof.
 19. A compoundaccording to claim 1, selected from the group consisting of:4-Chloro-[4-(2-{4-[2-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-[4-(2-{4-[2-((R)-3-ethoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide,1H-Indole-6-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide,4-Chloro-3-fluoro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-(4-{2-oxo-2-[4-(2-oxo-2-thiazolidin-3-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,[4-(2-{4-[2-(3-Amino-pyrrolidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-4-chloro-benzamide,4-Chloro-[4-(2-oxo-2-{4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide,4-Chloro-N-(4-{2-[4-(4,5-dihydro-thiazol-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,5-Bromo-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,5-Chloro-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,5-Chloro-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,3-Fluoro-4-methoxy-N!-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,4-Chloro-(4-{[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,4-Chloro-(4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,4-Chloro-(4-{[4-(1,1-dioxo-[1,2]thiazinan-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,4-Chloro-(4-{[4-(1,1-dioxo-isothiazolidin-2-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-benzamide,5-Methyl-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,4-Chloro-(4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide,5-Chloro-thiophene-2-carboxylic acid(4-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-amide,4-Chloro-N-(4-{2-oxo-2-[4-(pyridin-2-yloxy)-piperidin-1-yl]-ethyl}-thiazol-2-yl)-benzamide,5-Chloro-thiophene-2-carboxylic acid(4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide,5-Chloro-thiophene-2-carboxylic acid(4-{[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-methyl}-thiazol-2-yl)-amide,and any pharmaceutically acceptable salt thereof.
 20. A compoundaccording to claim 1, selected from the group consisting of:5-chloro-thiophene-2-carboxylic acid(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide;5-bromo-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide;5-chloro-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide;and any pharmaceutically acceptable salt thereof.
 21. A compoundaccording to claim 1 which is 5-chloro-thiophene-2-carboxylic acid(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide.22. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.